1. Field of the Invention
The present invention relates generally to the treatment of fungal infections in mammals. More particularly, the present invention provides methods of treating fungal infections in mammals using pharmaceutical preparations including chelator(s), antifungal agents, and/or monoclonal antibodies. The invention further provides pharmaceutical compositions useful for treating fungal infections.
2. Description of Related Art
Fungi, particularly species of Candida, Aspergillus, and Fusarium are a major cause of infection-related mortality in patients with leukemia and lymphoma. In addition, fungal infection is a major cause of mortality in patients with congenital and acquired deficiencies of the immune system.
For example, several species of Aspergillus are known to cause invasive sinopulmonary infections in seriously immunocompromised patients. Following inhalation of spores, clinical aspergillosis can occur in three major presentations. The first presentation, allergic bronchopulmonary aspergillosis, develops when Aspergillus species colonize the bronchial tree and release antigens that cause a hypersensitivity pneumonitis. The second presentation, aspergilloma or "fungus ball," develops in pulmonary cavities, often in concert with other lung diseases such as tuberculosis. The third form, invasive pulmonary or disseminated aspergillosis, is a life threatening infection with a high mortality rate.
The drug of choice in treatment of invasive aspergillosis, as well as in most other systemic mycoses, is Amphotericin B. Amphotericin B is a polyene antibiotic produced from a strain of Streptomyces nodosus. It is a lipophilic compound which binds to ergosterols in fungal membranes, resulting in the formation of transmembrane channels which allow the escape of metabolites essential to maintaining the viability of the fungal cell. Mammalian cell membranes also contain sterols, and it is believed that this same mechanism of action is responsible for the damaging effects which Amphotericin B is known to exert on mammalian kidney, hematopoietic and central nervous system tissues.
Amphotericin B is not soluble in aqueous solution, and for this reason it is supplied commercially in the form of a colloidal suspension comprising Amphotericin B, desoxycholate, and buffers suspended in a glucose solution. This suspension is usually administered to the patient intravenously over a period of from two to six hours; faster infusions can result in cardiorespiratory arrest. Other possible untoward effects of administering Amphotericin B include fever, nausea and vomiting, diarrhea, renal dysfunction, anemia, hypotension, headache, vertigo, and loss of hearing. Amphotericin B is also available in the form of a phospholipid complex (ABELCET.RTM., e.g.), which offers the advantage of somewhat reduced toxicity for those patients who do not tolerate free Amphotericin B well, although many of the same untoward side effects may be observed in patients receiving this lipid complex form of the drug.
As a consequence of the potential seriousness of its toxic side effects, there is a clear need for an alternative to treating systemic mycoses solely with Amphotericin B and/or other harsh antifungal agents.